Libraries of peptide conjugates and methods for making them

Abstract

The invention relates to peptide conjugates including at least one turn inducer wherein the turn inducer comprises a 5-7 membered saturated or unsaturated nitrogen containing heterocyclic ring and methods of making the peptides. Libraries of these peptides, methods of making the libraries are also described and methods of screening the libraries for therapeutic activity are also described.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to peptide conjugates including at least one turn inducer and methods of making such peptides. In particular, the present invention relates to such peptide conjugates and libraries thereof, which may possess therapeutic activity. The invention also relates to methods of preparing the libraries of peptide conjugates.BACKGROUND OF THE INVENTION[0002]A common method of approaching drug discovery is to identify a biochemical pathway that is operating in a pathological process and those steps that occur in the pathway that may be modulated to disrupt the pathological process. Assays that determine the ability of the enzymes or receptors in the pathway to function may then be used for screening a variety of compounds to identify those with potential therapeutic activity for the pathological condition. With high-throughput screening techniques, vast numbers of compounds may be assayed in a short period of time. The supply ...

AI Technical Summary

Benefits of technology

[0053]As used herein, the term “N-terminal capping group” refers to a group covalently bonded to the N-terminal nitrogen atom. The N-terminal capping group may assist in stabilizing the peptide conjugate in vivo or in vitro. For example, the N-terminal capping group may reduce hydrolysis by in vivo proteolytic enzymes or may reduce degradation of the peptide conjugate under storage conditions. The N-terminal capping group may assist in receptor binding providing substituents for further attractive binding in the receptor active site. The N-terminal capping group may also be chosen to allow penetration of the peptide conjugate to the site of activity, for example, through membranes, through the extracellular matrix or through cell walls. The N-terminal capping group may also be present to provide stabilization of the peptide conjugate through cyclization with the C-terminal capping group or a side chain of an amino acid residue in R1.

[0138]The safety catch linker allows the peptide to remain compartmentalized during cleavage of protecting groups, either stepwise or in one reaction. It also allows intensive washing procedures to remove products of side reactions and byproducts. This allows very clean assay-ready peptide conjugates to be produced.

[0223]The use of the SCAL linker and Lantern enables copious washing of the peptide conjugate while still attached to the linker. This enables the peptide conjugate to be isolated in a purified form with reduced byproducts present. In some cases the peptide conjugate is isolated after removal from the linker essentially free from byproducts.

[0239]It is also noted that norepinephrine transporter is expressed not only by nerve cells, but also by other tissues including the placenta, pulmonary endothelial cells and the uterus. The peptide conjugates of formula (VI) may also be effective in inhibiting these norepinephrine transporter, and may be useful in treating conditions in which these transporters are implicated.

Problems solved by technology

The supply of suitable compounds to assay becomes a rate-limiting step in the search for potential therapeutic agents.

However, despite the emergence of a number of turn mimetic technologies, there are few examples of drugs in clinical development derived from such platforms.

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